SUMMARY Diabetic bone disease, with its elevated risk for fragility fracture, is increasingly recognized as a distinct entity that cannot be assessed sufficiently with standard methods used for osteoporosis. Severe deficits in cortical bone structure, specifically increased cortical porosity, are associated with fracture prevalence in T2D. Cortical porosity has deleterious effects on bone strength, and is critical in fracture initiation and propagation. Despite the biomechanical importance of cortical porosity, the origins and temporal evolution of pathological cortical porosity in T2D are unknown. To develop treatments specifically targeted to the prevention or reversal of pathological cortical porosity and associated bone fragility in T2D, we must understand the mechanisms driving development of these large cortical pores. Today, these mechanisms are unknown though many have been posited, including endocortical `trabecularization' and expansion of the Haversian network. We hypothesize that determining the content and spatial distribution of cortical pore space will reveal biological systems influencing pore expansion. Marrow within pores near the endosteal border may indicate endocortical `trabecularization', or infiltration of the marrow cavity into the cortical envelope. Alternatively, vessels within pores distributed throughout the cortex may indicate pore formation via expansion of the vascular network. The identification of biological systems associated with pore expansion will elucidate appropriate cellular targets for drug development. The overall goal of this proposed study is to understand the longitudinal evolution of human diabetic bone disease and to investigate the underlying biological processes that drive increased cortical porosity in the setting of T2D. We propose the first longitudinal study of pore progression in T2D patients, which will be performed using a novel combined high-resolution peripheral quantitative computed tomography (HR-pQCT) and contrast enhanced magnetic resonance (MR) imaging approach, with the following aims: I: Determine if increased porosity in T2D is associated with altered marrow distribution and composition, II: Determine if increased porosity in T2D is associated with altered vessel distribution and vascular health, and III: Determine if T2D status or marrow or vessel metrics predict longitudinal increase in porosity and decrease in strength. To address aims I and II, we will perform multimodal imaging in a cross-sectional cohort of T2D patients and matched control subjects. To address aim III, we will follow these subjects in a 2-year longitudinal study. This work will establish whether cortical pore content can serve as a predictor of future cortical degradation, and begin to elucidate biological drivers and possible drug targets for the prevention or reversal of T2D-associated pathological porosity and bone fragility, laying the groundwork for future therapeutic studies. With the number of devastating diabetic fragility fractures increasing, these studies have the potential for immense clinical impact.